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  • Barth syndrome, also known as 3-methylglutaconic aciduria type II, is a rare X-linked disorder caused by defective activity of tafazzin, leading to abnormal cardiolipin remodeling and an abnormal composition of cardiolipin species in the inner mitochondrial membrane.

  • Cardiolipin is a phospholipid composed of two phosphatidyl groups linked to a glycerol backbone and four fatty acyl chains, synthesized in a several-step pathway. Cardiolipin is found primarily in the inner mitochondrial membrane and at contact sites between the inner and outer mitochondrial membrane.

  • Many physiologic functions have been assigned to cardiolipin including roles in maintaining mitochondrial structure, organizing mitochondrial supercomplexes, and in apoptosis. Cardiolipin has also been implicated in multiple disease processes including diabetes and obesity. The only known Mendelian disease associated with an abnormality in cardiolipin transacylation is Barth syndrome.

  • Major clinical features in Barth syndrome include cardiomyopathy, neutropenia, and skeletal, muscle, and growth abnormalities. Both the cardiomyopathy and neutropenia have an unpredictable waxing and waning severity throughout an individual’s lifetime.

  • Biochemical findings commonly found in individuals with Barth syndrome include: urine organic acids with increased 3-methylglutaconic acid, 3-methylglutaric acid, and 2-ethylhydracrylic acid, elevated plasma 3-methylglutaconic acid, and abnormal cardiolipin composition including decreased tetralinoleyl-cardiolipin and increased monolysocardiolipin in a variety of tissues. Other laboratory abnormalities include intermittent lactic acidemia, relatively reduced plasma arginine and elevated plasma proline, hypocholesterolemia, hypoglycemia, mild elevations in plasma creatine kinase, and reduced prealbumin. Female heterozygotes do not have detectable biochemical abnormalities.

  • Tafazzin (TAZ) is encoded by TAZ, an 11 exon gene located at Xq28. Mutations in TAZ found in affected males include: small insertions or deletions (16%), nonsense mutations (14%), missense mutations (48%), splicing (15%), and large exonic deletions (7%). No genotype-phenotype correlation has been observed, and penetrance is believed to be complete, with variable expressivity.


The discovery of TAZas the gene responsible for Barth syndrome was first reported in 1996.1 At the time of this discovery, this gene was named G4.5, and its function was unknown. The gene was renamed TAZ and the role of its protein product, tafazzin (TAZ), was uncovered four years later. TAZ was found to be important in the acyl chain remodeling of Cardiolipin (CL)(2).

CL was first isolated from bovine heart in 1942, (from which its name derives: Greek, kardia, for heart) as a substance with utility in the serologic test for syphilis.3 In 1964, the structure of CL was described.4 CL is a phospholipid with a unique structure composed of two phosphatidyl groups linked to a glycerol backbone and four fatty acyl chains (Figure 138-1). In 1975, the primary subcellular localization was determined to be mitochondrial.5 CL was later further localized to the inner mitochondrial membrane and at contact sites between the inner and outer mitochondrial membrane.6-8

Figure 138-1.

Structure of tetralinoleylcardiolipin.


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